The effect of idebenone, a coenzyme Q analogue, on hydrophobic bile acid toxicity to isolated rat hepatocytes and hepatic mitochondria

Shivaram, Kalugotla N; Winklhofer‐Roob, Brigitte M.; Straka, M S; Devereaux, Michael W.; Everson, Gregory T.; Mierau, Gary W.; Sokol, Ronald J.

doi:10.1016/s0891-5849(98)00077-x

Cited by 35 publications

(28 citation statements)

References 47 publications

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“…Effect of Ub 0 , Ub 5 and Ub 10 on H 2 O 2 production in U937 cells Ubiquinone analogs have been reported to either reduce or increase reactive oxygen species (ROS) formation (Seung et al 1998;Shivaram et al 1998). We have recently shown that ubiquinone analogs regulate ROS production in different ways according to the cell type, with effects that do not correlate with the way they regulate PTP opening (Devun et al 2010).…”

Section: Resultsmentioning

confidence: 95%

“…Decylubiquinone has been shown to prevent glutathion depressioninduced cell death in HL 60 cells (Armstrong et al 2003), idebenone to protect hepatocytes during hydrophobic bile acid toxicity (Shivaram et al 1998;Yerushalmi et al 2001), and coenzyme Q 10 (ubiquinone 50) to block apoptosis in neuronal PC12 cells exposed to ceramide or ethanol (Kagan et al 1999). In these studies, the effect of these quinones on PTP regulation has not been tested, and the protective effect has been attributed to antioxidant activity.…”

Section: Discussionmentioning

confidence: 99%

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Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death

Béllière

Devun

Cottet‐Rousselle

et al. 2012

J Bioenerg Biomembr

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The permeability transition pore (PTP) is a mitochondrial inner membrane channel involved in cell death. The inhibition of PTP opening has been proved to be an effective strategy to prevent cell death induced by oxidative stress. Several ubiquinone analogs are known to powerfully inhibit PTP opening with an effect depending on the studied cell line. Here, we have studied the effects of ubiquinone 0 (Ub(0)), ubiquinone 5 (Ub(5)) and ubiquinone 10 (Ub(10)) on PTP regulation, H(2)O(2) production and cell viability in U937 cells. We found that Ub(0) induced both PTP opening and H(2)O(2) production. Ub(5) did not regulate PTP opening yet induced H(2)O(2) production. Ub(10) potently inhibited PTP opening yet induced H(2)O(2) production. Both Ub(0) and Ub(5) induced cell death, whereas Ub(10) was not toxic. Moreover, Ub(10) prevented tert-butyl hydroperoxide-induced PTP opening and subsequent cell death. We conclude that PTP-inhibitor ubiquinone analogs are able to prevent PTP opening-induced cell death only if they are not toxic per se, which is the case when they have no or low pro-oxidant activity.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death

Béllière

Devun

Cottet‐Rousselle

et al. 2012

J Bioenerg Biomembr

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“…Thus, novel approaches to reduce the generation of mitochondrial-derived ROS or to prevent increases in mitochondrial Ca 2ϩ concentration may have a beneficial effect in human liver diseases associated with the accumulation of hydrophobic bile acids. The concentrations of bile acids achieved in the isolated hepatocyte experiments and used in the mitochondrial experiments in this study are in the range of those measured in liver from humans with cholestasis (1,65), making the findings reported of potential clinical relevance. The inhibition of the MMPT demonstrated in our study when antioxidants were added after mitochondrial exposure to GCDC suggests that this therapeutic strategy could be of potential benefit, even after the onset of cholestasis and the hepatic accumulation of bile acids.…”

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confidence: 58%

Role of Oxidant Stress in the Permeability Transition Induced in Rat Hepatic Mitochondria by Hydrophobic Bile Acids

et al. 2001

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Hydrophobic bile acids may cause hepatocellular necrosis and apoptosis during cholestatic liver diseases. The mechanism for this injury may involve mitochondrial dysfunction and the generation of oxidant stress. The purpose of this study was to determine the relationship of oxidant stress and the mitochondrial membrane permeability transition (MMPT) in hepatocyte necrosis induced by bile acids. The MMPT was measured spectrophotometrically and morphologically in rat liver mitochondria exposed to glycochenodeoxycholic acid (GCDC). Freshly isolated rat hepatocytes were exposed to GCDC and hepatocellular necrosis was assessed by lactate dehydrogenase release, hydroperoxide generation by dichlorofluorescein fluorescence, and the MMPT in cells by JC1 and tetramethylrhodamine methylester fluorescence on flow cytometry. GCDC induced the MMPT in a dose-and Ca 2ϩ -dependent manner. Antioxidants significantly inhibited the GCDC-induced MMPT and the generation of hydroperoxides in isolated mitochondria. Other detergents failed to induce the MMPT and a calpain-like protease inhibitor had no effect on the GCDC-induced MMPT. In isolated rat hepatocytes, GCDC induced the MMPT, which was inhibited by antioxidants. Blocking the MMPT in hepatocytes reduced hepatocyte necrosis and oxidant stress caused by GCDC. Oxidant stress, and not detergent effects or the stimulation of calpain-like proteases, mediates the GCDC-induced MMPT in hepatocytes. We propose that reducing mitochondrial generation of reactive oxygen species or preventing increases in mitochondrial Ca 2ϩ may protect the hepatocyte against bile acid-induced necrosis. 1-3). Although hydrophobic bile acids cause injury to isolated hepatocytes (4), cultured hepatocytes (5), and the intact liver (6), the mechanisms of this toxicity are not fully understood. Both hepatocellular necrosis at higher bile acid concentrations (4) and apoptosis at lower concentrations (7) have been demonstrated and are proposed as playing a role in cholestatic liver injury. Hepatocyte necrosis is characterized by cellular swelling, loss of mitochondrial respiratory function, depleted cellular ATP levels, and formation of plasma membrane blebs that rupture and release cellular contents (8, 9). In cholestatic liver ABSTRACT519

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“…A previous study showed stronger effects with pre- than with posttreatment [18]. Also, we [19] and others [20,21,22] showed promising results with pretreatment; therefore, we chose this regimen again for the present study.…”

Section: Methodsmentioning

confidence: 89%

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

et al. 2015

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Purpose: Age-related macular degeneration (AMD) is one of the leading causes of blindness. Degeneration of the retinal pigment epithelium (RPE) is pathognomonic for the disease, and oxidative stress plays an important role in the pathogenesis of this disease. This study investigates potential antiapoptotic and cytoprotective effects of idebenone on cultured RPE cells (ARPE-19) under conditions of oxidative stress. Methods: ARPE-19 cells were treated with 1-100 µM idebenone. Cell viability (MTT assay), induction of intracellular reactive oxygen species (ROS) and histone-associated DNA fragments in mono- and oligonucleosomes, expression of proapoptotic BAX and antiapoptotic Bcl-2 as well as senescence-associated β-galactosidase (SA-β-Gal) activity were investigated under exposure to hydrogen peroxide (H₂O₂). Results: Idebenone concentrations from 1 to 20 µM showed no toxic effects on ARPE-19 cells. When cells were treated with H₂O₂, pretreatment with 5, 7.5, 10, and 20 µM idebenone led to a significant increase in the viability of ARPE-19 cells. In addition, idebenone pretreatment significantly attenuated the induction of SA-β-Gal and intracellular ROS as well as the amount of histone-associated DNA fragments after treatment with H₂O₂. The reduction of proapoptotic BAX and the elevation of antiapoptotic Bcl-2 under idebenone show that this process is rather mediated by inhibiting H₂O₂-induced apoptosis, not necrosis. Conclusion: In this study, idebenone increased survival of ARPE-19 cells and reduced cell death, senescence, and oxidative stress by stabilizing the BAX/Bcl-2 ratio.

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The effect of idebenone, a coenzyme Q analogue, on hydrophobic bile acid toxicity to isolated rat hepatocytes and hepatic mitochondria

Cited by 35 publications

References 47 publications

Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death

Prerequisites for ubiquinone analogs to prevent mitochondrial permeability transition-induced cell death

Role of Oxidant Stress in the Permeability Transition Induced in Rat Hepatic Mitochondria by Hydrophobic Bile Acids

Idebenone Prevents Oxidative Stress, Cell Death and Senescence of Retinal Pigment Epithelium Cells by Stabilizing BAX/Bcl-2 Ratio

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